We have further characterized Zscan4 in mouse 2-cell embryos and in the subpopulation of mouse ES cells. We found that other 2-cell-specific genes are also highly expressed in Zscan4(+) cells. This indicates that the subpopulation of ES cells marked by Zscan4 expression shows some resemblance to 2-cell embryos, whereas the majority of ES cells show similarity to the Inner Cell Mass (ICM) cells in blastocysts. Zscan4 is thus associated with a unique transient state in undifferentiated ES cells, in which other 2-cell embryo-specific genes are activated. By carrying out cell lineage tracing experiments, we have found that, although Zscan4 is expressed only in 5% of ES cells in culture at a given time, essentially all the ES cells experience Zscan4-positive state by 9 passages. By knocking down Zscan4 activation by an shRNA, we have found that Zscan4 is essential for long-term maintenance of genomic integrity and to mediate a regulated telomere recombination in normal undifferentiated ES cells, therefore making it indispensable for proper long-term self-renewal in ES cells. We have also found that Zscan4 is involved in the induction and recruitment of the meiosis-specific homologous recombination machinery to telomeres. We are currently investigating whether the activation of Zscan4 can further increase the genome stability in ES and induced pluripotent (iPS) stem cells.